Using a high-throughput robotic system we plan to screen a library of 70,000 small molecules (each <700 daltons) for agonists at the secretin receptor transfected into cells. Small molecule non-peptide agonists at this receptor may overcome some of the anticipated issues with administration of the peptide hormone in the treatment of patients with Autistic disorders, such as its short in vivo half life, its need to be administered by injection and its pharmacokinetic parameters. We propose to: Clone and express the human secretin receptor in a Chinese Hamster Ovary cell line. Confirm transfection by showing secretin stimulated accumulation of cAMP only in the transfected cells. Demonstrate that we can obtain cells which respond to secretin (by increasing cAMP) in a dose-dependent manner and that show a maximal response to secretin at least 2 fold that of the un-transfected cells. Develop and validate an assay that detects an increase in cAMP levels in these cells by compounds acting as agonists at the secretin receptor. Using High Throughput Screening (HTS) robotics, screen for non-peptide small organic compounds from Psychiatric Genomics' (PGI) collection that can act as agonists at the secretin receptor and stimulate cAMP accumulation. PROPOSED COMMERCIAL APPLICATION: Patients with autism, or those within the broader category of autism spectrum disorder, are those who might benefit from secretin agonist drug therapy. A novel and innovative drug for autism would qualify under orphan drug status since there are less than 200,000 patients with autism in the U.S. This would increase the commercial viability and attractiveness of such a drug to small biotechnology or pharmaceutical businesses, and enhance the interest by the FDA.